Acryloyl chloride → N-{3-[(5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}prop-2-enamide

HRID 577679Notes

Reaction equation

HRID 577679 reaction equation
[NH2:1][CH:2]1[CH2:5][CH:4]([O:6][C:7]2[C:8]3[C:22]([C:23]#[N:24])=[CH:21][N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[N:12]=2)[CH2:3]1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([C:22]1[C:8]2[C:7]([O:6][CH:4]3[CH2:3][CH:2]([NH:1][C:33](=[O:36])[CH:34]=[CH2:35])[CH2:5]3)=[N:12][C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)=[N:10][C:9]=2[N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:21]=1)#[N:24]

Participants

5

Reactant 3

HCID 13140Acryloyl chlorideHCID 81531DiisopropylethylamineHCID 866796244-[(3-aminocyclobutyl)oxy]-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

Product 1

HCID 86679625N-{3-[(5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}prop-2-enamideYield 75%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 4-[(3-aminocyclobutyl)oxy]-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (cis:trans 1:1) (380 mg, 0.84 mmol) in DCM (10 mL) was added acryloyl chloride (68 μL, 0.84 mmol) and DIPEA (146 μL, 0.84 mmol). The reaction solution was stirred at rt for 10 min. The reaction mixture was partitioned between DCM (50 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was separated, dried over Na2SO4 and evaporated. The product was purified via flash chromatography eluting with a gradient of 0%-100% EtOAc in heptanes to give the title compound (317 mg, 75% yield) as a 1:1 cis:trans isomeric mixture. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (s, 1H) 8.42-8.63 (m, 1H) 8.11 (s, 1H) 7.96 (br. s., 1H) 7.43-7.62 (m, 1H) 6.00-6.31 (m, 2H) 5.61 (ddd, J=9.69, 7.05, 2.64 Hz, 3H) 4.07-5.26 (m, 2H) 3.81 (d, J=5.79 Hz, 3H) 3.56 (t, J=7.93 Hz, 2H) 2.84-2.99 (m, 1H) 2.51-2.58 (m, 2H) 2.08-2.20 (m, 1H) 0.84 (t, J=8.06 Hz, 2H) −0.12 (br. s., 9H). m/z (APCI+) for C24H32N8O3Si 509.1 (M+H)+.

Workup

  1. customThe reaction mixture was partitioned between DCM (50 mL) and saturated aqueous NaHCO3 (20 mL)
  2. customThe organic layer was separated
  3. dry with materialdried over Na2SO4
  4. customevaporated
  5. customThe product was purified via flash chromatography
  6. washeluting with a gradient of 0%-100% EtOAc in heptanes

Sources & evidence

ORD record
ord-6f4309b64db74586a4e8bcff77d2895d
Source dataset
uspto-grants-2015_05
Patent number
US09040547B2

Reaction notes

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